Expression of inhibitor proteins that control primordial follicle reserve decreases in cryopreserved ovaries after autotransplantation

Celik, Soner; Çelikkan, Ferda Topal; Özkavukçu, Sinan; Can, Alp; Çelik-Özenci, Çiler

doi:10.1007/s10815-018-1140-6

Cited by 15 publications

(8 citation statements)

References 44 publications

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“…SonerCelik et al [60] research team's findings regarding ovarian cryo-preservation and auto-transplantation demonstrate that expression of inhibitor proteins that control primordial follicle reserve decreases in cryopreserved ovaries after transplantation. The observation is consistent with the ovarian activity rush observed by others [61,62], and thus they debate the recommendation of follicular activation prior (in vitro activation IVA) to transplantation [58,63]. The longevity of the transplanted ovarian tissue varies widely and may depend on the age of the woman at cryo-preservation [64], some blaming the revascularization rate after transplantation as an important issue [65]; however, long functioning viability of more than ten years has been reported [66].…”

Section: New Techniques Of Fertility Preservationsupporting

confidence: 82%

State of the Art in Fertility Preservation for Female Patients Prior to Oncologic Therapies

Chibelean

Petca

Radu³

et al. 2020

Medicina

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Quality of life improvement stands as one of the main goals of the medical sciences. Increasing cancer survival rates associated with better early detection and extended therapeutic options led to the specific modeling of patients’ choices, comprising aspects of reproductive life that correlated with the evolution of modern society, and requires better assessment. Of these, fertility preservation and ovarian function conservation for pre-menopause female oncologic patients pose a contemporary challenge due to procreation age advance in evolved societies and to the growing expectations regarding cancer treatment. Progress made in cell and tissue-freezing technologies brought hope and shed new light on the onco-fertility field. Additionally, crossing roads with general fertility and senescence studies proved highly beneficial due to the enlarged scope and better synergies and funding. We here strive to bring attention to this domain of care and to sensitize all medical specialties towards a more cohesive approach and to better communication among caregivers and patients.

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Section: New Techniques Of Fertility Preservationsupporting

confidence: 82%

State of the Art in Fertility Preservation for Female Patients Prior to Oncologic Therapies

Chibelean

Petca

Radu³

et al. 2020

Medicina

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“…A major obstacle of OTCTP is follicle loss due to, among other factors, accelerated recruitment of primordial follicles during the transplantation process [ 18 , 53 , 54 ]. Our first aim was to assess how cryopreservation itself impacts follicle activation.…”

Section: Discussionmentioning

confidence: 99%

“…Follicle activation after OTCTP is well documented in both preclinical and clinical studies [47][48][49][50][51][52]. The transplantation process itself is the major cause of accelerated recruitment of primordial follicles, and the PI3K/PTEN/ Akt and mTOR pathways are the main pathways involved in this phenomenon [18,53,54]. However, the contribution of the cryopreservation process to follicle activation is not yet well studied.…”

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confidence: 99%

Pharmacological inhibition of the PI3K/PTEN/Akt and mTOR signalling pathways limits follicle activation induced by ovarian cryopreservation and in vitro culture

2021

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Background Cryopreservation and transplantation of ovarian tissue (OTCTP) represent a promising fertility preservation technique for prepubertal patients or for patients requiring urgent oncological management. However, a major obstacle of this technique is follicle loss due to, among others, accelerated recruitment of primordial follicles during the transplantation process, leading to follicular reserve loss in the graft and thereby potentially reducing its lifespan. This study aimed to assess how cryopreservation itself impacts follicle activation. Results Western blot analysis of the PI3K/PTEN/Akt and mTOR signalling pathways showed that they were activated in mature or juvenile slow-frozen murine ovaries compared to control fresh ovaries. The use of pharmacological inhibitors of follicle signalling pathways during the cryopreservation process decreased cryopreservation-induced follicle recruitment. The second aim of this study was to use in vitro organotypic culture of cryopreserved ovaries and to test pharmacological inhibitors of the PI3K/PTEN/Akt and mTOR pathways. In vitro organotypic culture-induced activation of the PI3K/PTEN/Akt pathway is counteracted by cryopreservation with rapamycin and in vitro culture in the presence of LY294002. These results were confirmed by follicle density quantifications. Indeed, follicle development is affected by in vitro organotypic culture, and PI3K/PTEN/Akt and mTOR pharmacological inhibitors preserve primordial follicle reserve. Conclusions Our findings support the hypothesis that inhibitors of mTOR and PI3K might be an attractive tool to delay primordial follicle activation induced by cryopreservation and culture, thus preserving the ovarian reserve while retaining follicles in a functionally integrated state.

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“…Related to ischemia or not, the balance between activator and suppressor molecules in the ovary that normally keeps the dormant PFs from depletion is suggested to change instantly and a rapid burn-out leads to a significant follicle loss after OTC causing premature ovarian failure (POF) [13]. The authors recently showed that expression of inhibitor proteins, which control primordial follicle reserve, decreases in cryopreserved ovaries after autotransplantation [14]. Primordial follicles are aroused from a quiescence state by the interaction of various molecules to activate the PF growth, such as growth differentiation factor-9 (GDF-9), bone morphogenic protein-4/7/15 (BMP-4/7/15), Kit-ligand (KITL), leukemia inhibitory factor (LIF), and fibroblast growth factor (FGF-2), which are expressed in oocytes, granulosa cells, and stroma cells [13].…”

Section: Introductionmentioning

confidence: 99%

“…In recent studies on mice, it has been shown that rapamycin inhibits PF growth [21] and reverses the symptoms of ovarian hyperstimulation syndrome (OHSS) [22]. Based on the authors' recent findings about disrupted expression of inhibitor proteins after OTC and transplantation [14], the aim of this study was to investigate the effect of OTC on the expression of activator proteins that control follicle reserve and the protective potential of rapamycin treatment on PFs after vitrification/warming and re-transplantation in rats. As recent studies have demonstrated the importance of mTOR signaling pathway on PF survival and recruitment after various conditions [23], it was investigated whether PF burn-out after post-thaw and posttransplantation could be prevented by inhibiting the mTOR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Altered expression of activator proteins that control follicle reserve after ovarian tissue cryopreservation/transplantation and primordial follicle loss prevention by rapamycin

Celik

Özkavukçu

Çelik-Özenci

2020

J Assist Reprod Genet

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Purpose We investigated whether expression of activator proteins that control follicle reserve and growth change after ovarian tissue vitrification and re-transplantation. Moreover, we assessed whether inhibition of mTOR signaling pathway by rapamycin would protect primordial follicle reserve after ovarian tissue freezing/thawing and re-transplantation. Methods Fresh control, frozen/thawed, fresh-transplanted, frozen/thawed and transplanted, rapamycin/control, rapamycin freshtransplanted, and rapamycin frozen-thawed and transplanted groups were established in rats. After freezing and thawing process, two ovaries were transplanted into the back muscle of the same rat. After 2 weeks, grafts were harvested, fixed, and embedded into paraffin block. Normal and atretic primordial/growing follicle count was performed in all groups. Ovarian tissues were evaluated for the dynamic expressions of Gdf-9, Bmp-15, KitL, Lif, Fgf-2, and p-s6K using immunohistochemistry, and H-score analyses were done. Results Primordial follicle reserve reduced almost 50% after ovarian tissue re-transplantation. Expression of Gdf-9 and Lif increased significantly in primordial and growing follicles in frozen-thawed, fresh-transplanted, and frozen/thawed and transplanted groups, whereas expression of Bmp-15, KitL, and Fgf-2 decreased in primordial follicles. Freezing and thawing of ovarian tissue solely significantly increased p-s6K expression in primordial follicles, and on the other hand, suppression of mTORC1 pathway using rapamycin preserved the primordial follicle pool. Conclusion Altered expressions of activator proteins that regulate primordial follicle reserve and growth may lead to primordial follicle loss and rapamycin treatment can protect ovarian reserve after ovarian tissue cryopreservation/transplantation.

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Expression of inhibitor proteins that control primordial follicle reserve decreases in cryopreserved ovaries after autotransplantation

Cited by 15 publications

References 44 publications

State of the Art in Fertility Preservation for Female Patients Prior to Oncologic Therapies

State of the Art in Fertility Preservation for Female Patients Prior to Oncologic Therapies

Pharmacological inhibition of the PI3K/PTEN/Akt and mTOR signalling pathways limits follicle activation induced by ovarian cryopreservation and in vitro culture

Altered expression of activator proteins that control follicle reserve after ovarian tissue cryopreservation/transplantation and primordial follicle loss prevention by rapamycin

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